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CARDIAC, RENAL, AND RESPIRATORY INTEGRATION

Impaired substance P release from renal sensory nerves in SHR involves a pertussis toxin-sensitive mechanism

Departments of Internal Medicine and Pharmacology, Department of Veterans Affairs Medical Center, and University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242

Submitted 27 August 2003 ; accepted in final form 16 October 2003

Stretching the renal pelvic wall activates renal mechanosensory nerves by a PGE₂-mediated release of substance P via activation of the cAMP-PKA pathway. Renal pelvic ANG II modulates the responsiveness of renal sensory nerves by suppressing the PGE₂-mediated activation of adenylyl cyclase via a pertussis toxin (PTX)-sensitive mechanism. In SHR, activation of renal mechanosensory nerves is impaired. This is due to suppressed release of substance P in response to increased pelvic pressure. The present study was performed to investigate whether the PGE₂-mediated release of substance P was suppressed in SHR vs. WKY and, if so, whether the impaired PGE₂-mediated release of substance P was due to ANG II activating a PTX-sensitive mechanism. In an isolated renal pelvic wall preparation, PGE₂, 0.14 µM, increased substance P release from 9 ± 3 to 22 ± 3 pg/min (P < 0.01) in Wistar-Kyoto rats (WKY), but had no effect in spontaneously hypertensive rats (SHR). A tenfold higher concentration of PGE₂, 1.4 µM, was required to increase substance P release in SHR, from 7 ± 1 to 22 ± 3 pg/min (P < 0.01). In SHR, treating renal pelvises with losartan enhanced the release of substance P produced by subthreshold concentration of PGE₂, 0.3 µM, from 16 ± 2 to 26 ± 3 pg/min (P < 0.01). Likewise, treating renal pelvises with PTX enhanced the PGE₂-mediated release of substance P from 10 ± 1 to 33 ± 3 pg/min (P < 0.01) in SHR. In WKY, neither losartan nor PTX had an effect on the release of substance P produced by subthreshold concentrations of PGE₂, 0.03 µM. In conclusion, the impaired responsiveness of renal sensory nerves in SHR involves endogenous ANG II suppressing the PGE₂-mediated release of substance P via a PTX-sensitive mechanism.

angiotensin; losartan; afferent renal nerves; renal pelvis; prostaglandin E₂

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